With the aim of understanding the mechanisms of evolution of genes and populations and of maintenance of genetic variability within populations, two' mutually related research projects are Proposed. (1) Evolutionary changes of genes and Populations. New statistical methods for estimating the total number of nucleotide substitutions and the numbers of synonymous and nonsynonymous substitutions will be developed by taking into account unequal nucleotide frequencies between different DNA sequences, variation in substitution rate among different nucleotide sites, etc. Efforts will also be made to find a simple but efficient method for estimating a phylogenetic tree and to develop statistical methods for testing topological and branch lengths differences of different trees estimated. The genetic and evolutionary relationships of various human populations will also be studied by using our large collection of gene frequency data as well as new statistical methods. (2) Evolutionary dynamics of genetic diversity. To .resolve controversies in evolution such as the origin of modern humans, mathematical and computer simulation studies will be conducted about the expected persistence (coalescence) time of polymorphic alleles and the fixation time of an advantageous mutation in subdivided populations. This study will also be important for understanding the evolution of pathogenicity of bacteria and other microorganisms. Computer simulation study as well as data analysis will be made to understand the factors (especially overdominant selection and gene conversion) that cause the extremely high degree of polymorphism at the major histocompatibility complex loci (MHC). Furthermore, the pattern of nucleotide substitution in the antigen recognition site of MHC genes will be studied to determine whether the molecular clock applies even to a region of gene where balancing selection operates. The extent and pattern of nucleotide variation in antigenic genes of parasitic protozoans such as Plasmodium, Trypasonoma, etc., will also be studied with the aim of understanding the coevolution of host immune system genes (MHC, T-cell receptor, immunoglobulins, etc.) and antigenic genes of parasites.